Electrical impedance myography in facioscapulohumeral muscular dystrophy

Introduction: In this study we determined the reliability and validity of electrical impedance myography (EIM) in facioscapulohumeral muscular dystrophy (FSHD). Methods: We performed a prospective study of EIM on 16 bilateral limb and trunk muscles in 35 genetically defined and clinically affected FSHD patients (reliability testing on 18 patients). Summary scores based on body region were derived. Reactance and phase (50 and 100 kHz ) were compared with measures of strength, FSHD disease severity, and functional outcomes. Results: Participants were mostly men, mean age 53.0 years, and included a full range of severity. Limb and trunk muscles showed good to excellent reliability [intraclass correlation coefficients (ICC) 0.72–0.99]. Summary scores for the arm, leg, and trunk showed excellent reliability (ICC 0.89–0.98). Reactance was the most sensitive EIM parameter to a broad range of FSHD disease metrics. Conclusions: EIM is a reliable measure of muscle composition in FSHD that offers the possibility to serially evaluate affected muscles. Muscle Nerve 54 : 696–701, 2016     

Facioscapulohumeral muscular dystrophy functional composite outcome measure

Introduction: We developed an evaluator‐administered functional facioscapulohumeral muscular dystrophy composite outcome measure (FSHD‐COM) comprising patient‐identified areas of functional burden for future clinical trials. Methods: We performed a prospective observational study of 41 patients with FSHD at 2 sites. The FSHD‐COM includes functional assessment of the legs, shoulders and arms, trunk, hands, and balance/mobility. We determined the test‐retest reliability and convergent validity compared to established FSHD disease metrics. Results: The FSHD‐COM demonstrated excellent test‐retest reliability (intraclass correlation coefficient [ICC] 0.96; subscale ICC range, 0.90–0.94). Cross‐sectional associations between the FSHD‐COM and disease duration, clinical severity, and strength were moderate to strong (Pearson correlation coefficient range |0.51–0.92|). Discussion: The FSHD‐COM is a disease‐relevant, functional composite outcome measure suitable for future FSHD clinical trials that shows excellent test‐retest reliability and cross‐sectional associations to disease measures. Future directions include determining multisite reliability, sensitivity to change, and the minimal clinically important change in the FSHD‐COM. Muscle Nerve 58 : 72–78, 2018     

Whole‐body magnetic resonance imaging evaluation of facioscapulohumeral muscular dystrophy

Introduction: Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary disorder that causes progressive muscle wasting. Increasing knowledge of the pathophysiology of FSHD has stimulated interest in developing biomarkers of disease severity. Methods: Two groups of MRI scans were analyzed: whole‐body scans from 13 subjects with FSHD; and upper and lower extremity scans from 34 subjects with FSHD who participated in the MYO‐029 clinical trial. Muscles were scored for fat infiltration and edema‐like changes. Fat infiltration scores were compared with muscle strength and function. Results: The analysis revealed a distinctive pattern of both frequent muscle involvement and frequent sparing in FSHD. Averaged fat infiltration scores for muscle groups in the legs correlated with quantitative muscle strength and 10‐meter walk times. Conclusions: Advances in MRI technology allow for acquisition of rapid, high‐quality, whole‐body imaging in diffuse muscle disease. This technique offers a promising disease biomarker in FSHD and other muscle diseases. Muscle Nerve 52: 512–520, 2015     

Bone health in facioscapulohumeral muscular dystrophy: A cross‐sectional study

Introduction: Herein we provide a comprehensive overview of bone health in facioscapulohumeral muscular dystrophy (FSHD). Methods : Ninety‐four adult individuals with FSHD type 1 from 2 sites were included in this cross‐sectional study. Clinical characteristics and determinants of bone health were examined. Relationships between bone mineral density (BMD), strength, and function were explored. Results : Nearly a third of subjects were deficient in vitamin D₃. Mean whole‐body BMD z‐score was ?0.7; 11% of subjects had greater than age‐related reductions in whole‐body BMD (z‐score < ?2.0). Whole‐body and regional BMDs were associated with strength and function. Thirty‐six percent had a history of fractures. Likelihood of fractures was reduced for those with normal whole‐body BMD (odds ratio = 0.25, 95% confidence interval 0.04–0.78). Discussion : A diagnosis of FSHD is not necessarily predictive of reduced BMD or increased fracture rate. Given the considerable variability of bone health in the FSHD population, strength and function can serve as predictors of BMD. Muscle Nerve 56 : 1108–1113, 2017     

Validity of the 6 minute walk test in facioscapulohumeral muscular dystrophy

Introduction: In preparation for future clinical trials, we determined the reliability, relationship to measures of disease severity, and consistency across sites of the 6 Minute Walk Test (6MWT) in patients with facioscapulohumeral muscular dystrophy (FSHD). Methods: Genetically defined and clinically affected FSHD participants at 2 sites performed the 6MWT, the Timed Up and Go, and the 30 foot Go/Timed 10 meter test as measures of mobility using standard procedures. Results: Eight‐six participants representing the full range of severity performed the 6MWT. The mean 6MWT distance was 404.3 meters (SD 123.9), with no difference between sites. The 6MWT was reliable (n = 25; intraclass correlation coefficient = 0.99) and demonstrated moderate to strong correlations with lower extremity strength, functional outcomes, and FSHD Clinical Score. Conclusions: The 6MWT is reliable and is associated with other measures of FSHD disease severity. Future directions include assessing its sensitivity to disease progression. Muscle Nerve 55 : 333–337, 2017     

MRI change metrics of facioscapulohumeral muscular dystrophy: Stir and T1

Introduction: MRI evaluation in facioscapulohumeral muscular dystrophy (FSHD) demonstrates fatty replacement and inflammation/edema in muscle. Our previous work demonstrated short T1 inversion recovery (STIR)‐hyperintense (STIR+) signal in muscle 2 years before fatty replacement. We evaluated leg muscle STIR changes and fatty replacement within 14 months. Methods: FSHD subjects received 2 MRI scans of thigh and calf over a 6.9‐ to 13.8‐month interval. Quality of life measures were collected. One Radiologist rated muscle changes on a semi‐quantitative scale. Results: Fifteen subjects completed longitudinal imaging. Four STIR + muscles and 3 STIR‐normal (STIR?) muscles were rated as progressing to fatty tissue over the study period. Discussion: STIR + muscles with confluent regions of fat at baseline increased more in fat, while STIR? muscles had increases in septal‐fat over the study period. These changes may reflect two phases of FSHD, demonstrating MRI sensitivity is weighted toward gross pathological phases of the disease. Muscle Nerve 57 : 905–912, 2018     

Muscle pathology grade for facioscapulohumeral muscular dystrophy biopsies

Introduction: As we move toward planning for clinical trials in facioscapulohumeral muscular dystrophy (FSHD), a better understanding of the clinical relationship with morphological changes in FSHD muscle biopsies will be important for stratifying patients and understanding post‐therapeutic changes in muscle. Methods: We performed a prospective cross‐sectional study of quadriceps muscle biopsies in 74 genetically confirmed FSHD participants (64 with FSHD type 1 and 10 with FSHD type 2). We compared a 12‐point muscle pathology grade to genetic mutation, disease severity score, and quantitative myometry. Results: Pathology grade had moderate correlations with genetic mutation (rho = –0.45, P < 0.001), clinical severity score (rho = 0.53, P < 0.001), disease duration (rho = 0.31, P = 0.03), and quantitative myometry (rho = –0.47, P < 0.001). We found no difference in the frequency of inflammation between FSHD types 1 and 2. Conclusions: The pathology grade of quadriceps muscle may be a useful marker of disease activity in FSHD, and it may have a role in stratification for future clinical trials. Muscle Nerve 52: 521–526, 2015     

Longitudinal 2‐point dixon muscle magnetic resonance imaging in becker muscular dystrophy

Introduction: Quantitative MRI techniques detect disease progression in myopathies more sensitively than muscle function measures or conventional MRI. To date, only conventional MRI data using visual rating scales are available for measurement of disease progression in Becker muscular dystrophy (BMD). Methods: In 3 patients with BMD (mean age 36.8 years), the mean fat fraction (MFF) of the thigh muscles was assessed by MRI at baseline and at 1‐year follow‐up using a 2‐point Dixon approach (2PD). The motor function measurement scale (MFM) was used for clinical assessment. Results: The mean MFF of all muscles at baseline was 61.6% (SD 7.6). It increased by 3.7% to 65.3% (SD 4.7) at follow‐up. The severity of muscle involvement varied between various muscle groups. Conclusions: As in other myopathies, 2PD can quantify fatty muscle degeneration in BMD and can detect disease progression in a small sample size and at relatively short imaging intervals. Muscle Nerve 51 : 918–921, 2015     

Patient‐identified disease burden in facioscapulohumeral muscular dystrophy

Introduction: The multitude of symptoms associated with facioscapulohumeral muscular dystrophy (FSHD) disease burden are of varying importance. The extent of these symptoms and their cumulative effect on the FSHD population is unknown. Methods: We conducted interviews with adult FSHD patients to identify which symptoms have the greatest effect on their lives. Each interview was recorded, transcribed, coded, and analyzed using a qualitative framework technique, triangulation, and a three‐investigator consensus approach. Results: One thousand three hundred seventy‐five quotes were obtained through 20 patient interviews. Two hundred fifty‐one symptoms of importance were identified representing 14 themes of FSHD disease burden. Symptoms associated with mobility impairment, activity limitation, and social role limitation were most frequently mentioned by participants. Conclusions: There are multiple themes and symptoms, some previously underrecognized, that play a key role in FSHD disease burden. Muscle Nerve, 2012     

Electrical impedance myography for the in vivo and ex vivo assessment of muscular dystrophy (mdx) mouse muscle

Introduction: Sensitive, non‐invasive techniques are needed that can provide biomarkers of disease status and the effects of therapy in muscular dystrophy. Methods: We evaluated electrical impedance myography (EIM) to serve in this role by studying 2‐month‐old and 18‐month‐old mdx and wild‐type (WT) animals (10 animals in each of 4 groups). Results: Marked differences were observed in EIM values between mdx and WT animals; the differences were more pronounced between the older age groups (e.g., reactance of 92.6 ±4.3 Ω for mdx animals vs. 130 ± 4.1 Ω for WT animals, P < 0.001). In addition, in vivo EIM parameters correlated significantly with the extent of connective tissue deposition in the mdx animals. Conclusions: EIM has the potential to serve as a valuable non‐invasive method for evaluating muscular dystrophy. It can be a useful biomarker to assist with therapeutic testing in both pre‐clinical and clinical studies. Muscle Nerve 49 : 829–835, 2014     

Quantitative muscle ultrasound versus quantitative magnetic resonance imaging in facioscapulohumeral dystrophy

Introduction: Ultrasound and magnetic resonance imaging (MRI) are non‐invasive methods that can be performed repeatedly and without discomfort. In the assessment of neuromuscular disorders it is unknown if they provide complementary information. In this study we tested this for patients with facioscapulohumeral muscular dystrophy (FSHD). Methods: We performed quantitative muscle ultrasound (QMUS) and quantitative MRI (QMRI) of the legs in 5 men with FSHD. Results: The correlation between QMUS‐determined z‐scores and QMRI‐determined muscle fraction and T1 signal intensity (SI) was very high. QMUS had a wider dynamic range than QMRI, whereas QMRI could detect inhomogeneous distribution of pathology over the length of the muscles. Conclusions: Both QMUS and QMRI are well suited for imaging muscular dystrophy. The wider dynamic range of QMUS can be advantageous in the follow‐up of advanced disease stages, whereas QMRI seems preferable in pathologies such as FSHD that affect deep muscle layers and show inhomogeneous abnormality distributions. Muscle Nerve 50: 968–975, 2014     

An instrumented timed up and go in facioscapulohumeral muscular dystrophy

Introduction: Instrumenting timed functional motor tasks may reveal a continuum of motor disability that predicts future motor dysfunction. Methods: We performed a prospective study of the instrumented timed up and go (iTUG) test in genetically confirmed facioscapulohumeral muscular dystrophy (FSHD) participants using a commercially available system of wireless motion sensors. Patients returned within 2 weeks to determine test–retest reliability. Gait parameters in FSHD participants were compared with a normative database, FSHD clinical severity score, manual muscle testing, and patient‐reported functional disability. Results: Gait parameters in FSHD participants were significantly (P < 0.05) altered compared with normative values, and reliability was excellent (intraclass correlation coefficient 0.84–0.99). Stride velocity and trunk sagittal range of motion had moderate to strong correlations to other FSHD disease measures. Discussion: The iTUG was reliable, abnormal in FSHD, and could distinguish between participants with differing disease severities. Instrumenting timed functional tasks may prove to be useful in FSHD clinical trials. Muscle Nerve 57 : 503–506, 2018     

Longitudinal features of stir bright signal in FSHD1

Introduction: Magnetic resonance imaging of muscle shows short tau‐inversion recovery (STIR) brightness in autosomal dominant facioscapulohumeral muscular dystrophy (FSHD1) suggestive of active inflammation/injury. We measured the longitudinal stability/progression of this potential disease biomarker. Methods: Nine subjects underwent calf MRI imaging over 2 years. Two radiologists evaluated qualitative muscle changes. Results: In 3/9 subjects, calf muscles demonstrated moderate/severe STIR hyperintensity at Time 1 that had progressed to fatty replacement 2 years later (Time 2). In the remaining subjects, moderate/severe muscle STIR abnormalities, when present, were consistent between exams. Mild STIR+ elevations had roughly similar patterns between exams. Conclusions: Moderate/severe STIR hyperintensities often foreshadow fatty replacement over a 2‐year interval. Whether longer time courses are required to observe muscle degeneration and fatty replacement in some subjects remains to be explored. Muscle Nerve 49 : 257–260, 2014     

Clinical trial readiness in non‐ambulatory boys and men with duchenne muscular dystrophy: MDA–DMD network follow‐up

Introduction: Outcomes sensitive to change over time in non‐ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well‐established. Methods: Subjects (n = 91; 16.8 ± 4.5 years old) were assessed at baseline and 6‐month intervals for 2 years. We analyzed all subjects using an intent‐to‐treat model and a subset of stronger subjects with Brooke Scale score ≤4, using repeated measures. Results: Eight patients (12–33 years old) died during the study. Sixty‐six completed 12‐month follow‐up, and 51 completed 24‐month follow‐up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. Forced vital capacity percent predicted (FVC% predicted) declined significantly only after 2 years. However, Brooke and Egen Klassifikation (EK) Scale scores, elbow flexion, and grip strength declined significantly over both 1 and 2 years. Conclusion: Brooke and EK Scale scores, elbow flexion, and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non‐ambulatory DMD subjects but did not affect decline rates of measures tested here. Muscle Nerve 54 : 681–689, 2016     

Cardiac involvement in Dutch patients with sarcoglycanopathy: A cross‐sectional cohort and follow‐up study

Introduction: The aim of this study is to describe the frequency, nature, severity, and progression of cardiac abnormalities in a cohort of Dutch sarcoglycanopathy patients. Methods: In this cross‐sectional cohort study, patients were interviewed using a standardized questionnaire and assigned a functional score. Electrocardiography (ECG), echocardiography, and 24‐h ECG were performed. Results: Twenty‐four patients with sarcoglycanopathy had a median age of 25 years (range, 8–59 years). Beta blockers were used by 13%, and 17% used angiotensin‐converting enzyme inhibitors. ECG abnormalities were present in 5 (21%), and 4 (17%) fulfilled the criteria for dilated cardiomyopathy (DCM). There were no significant differences in median age or severity of disease between patients with or without DCM. Eleven patients were examined earlier. Median follow‐up time was 10 years. Two of the 11 patients (18%) developed DCM during follow‐up. Conclusions: Seventeen percent of the patients with sarcoglycanopathy were found to have dilated cardiomyopathy. We recommend biannual cardiac monitoring, including ECG and echocardiography. Muscle Nerve 50 : 909–913, 2014     

The cardiorespiratory response and physiological determinants of the assisted 6‐minute handbike cycle test in adult males with muscular dystrophy

Introduction: The assisted 6‐minute cycle test (A6MCT) distance was assessed in adults with muscular dystrophy (MD). Methods: Forty‐eight males, including those with Duchenne MD (DMD), limb‐girdle MD (LGMD), fascioscapulohumeral MD (FSHD), and Becker MD (BMD), as well as a group without MD (CTRL), completed handgrip strength (HGS), lung function [forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC)], body fat, and biceps thickness assessments. During the A6MCT, ventilation (VE ), oxygen uptake (VO ₂), carbon dioxide (VCO ₂), and heart rate (HR) were recorded. Results: A6MCT and HGS were lower in MD than CTRL subjects. FEV₁, FVC, and biceps thickness were lower in MD than CTRL; lower in DMD than BMD, LGMD, and FSHD; but were not different between BMD, LGMD, and FSHD. A6MCT correlated with HGS, FEV₁, FVC, body fat, VO ₂, VCO ₂, HR, and VE (r = 0.455–0.708) in pooled BMD, LGMD, and FSHD participants. Discussion: A shorter A6MCT distance in adult males with MD was attributable to HGS and lung function. The A6MCT is appropriate for assessment of physical function in adults with MD. Muscle Nerve 58 : 427–433, 2018     

Magnetic resonance imaging in duchenne muscular dystrophy: Longitudinal assessment of natural history over 18 months

Introduction: In Duchenne muscular dystrophy (DMD), fat replacement of muscle may be a useful endpoint in trials of therapy, although progression in different muscle groups is uneven. In this study we assessed the progression of fat replacement with T₁‐weighted imaging over 2 9‐month periods. Methods: Eight ambulant, corticosteroid‐treated boys with DMD were imaged at 3 Tesla at 3 time‐points (baseline and 9 and 18 months) with T₁‐weighted imaging to measure fat replacement. Results: The greatest increase in fat content was measured in the biceps femoris long head, vastus lateralis, and rectus femoris, whereas the biceps femoris short head and gluteus maximus progressed more slowly. None of the lower leg muscles studied changed significantly. Conclusions: MRI can measure specific changes in fat replacement of muscle over time, demonstrating the variability in rates of natural progression between muscle groups and identifying those muscles suitable for use as biomarkers in clinical trials. Muscle Nerve 48 : 586–588, 2013     

Electrical impedance myography correlates with standard measures of Als severity

Introduction: Electrical impedance myography (EIM) can be used to assess amyotrophic lateral sclerosis (ALS) progression. The relationship between EIM values and standard assessment measures, however, is unknown. Methods: EIM 50 kHz phase data from 60 subjects who participated in a longitudinal natural history study of ALS were correlated with handheld dynamometry (HHD), the ALS Functional Rating Scale‐Revised (ALSFRS‐R) score, and motor unit number estimation (MUNE). Results: Moderate strength correlations between EIM parameters and HHD were observed for both whole‐body and individual upper and lower extremity values. Similarly, moderate strength correlations were observed between EIM and ALSFRS‐R upper and lower extremity subscores, but not total ALSFRS‐R scores. MUNE correlated significantly with single muscle EIM data but not with whole body or upper or lower extremity values. Conclusions: These results support the concept that EIM can serve as a meaningful measure of disease severity in ALS. Muscle Nerve 49 :441–443, 2014     

Quality of life and pain in patients with facioscapulohumeral muscular dystrophy

The aim of this study was to assess quality of life (QoL) and evaluate the occurrence and characteristics of pain in facioscapulohumeral muscular dystrophy (FSHD) patients. No study has yet assessed QoL in a large group of FSHD patients and, overall, few studies have assessed pain in neuromuscular diseases. We performed a prospective study using a multidimensional protocol including: clinical (according to the Clinical Severity Scale Rev1); genetic (p13E‐11 EcoRI fragments Rev1); QoL (Short Form‐36); pain (Visual Analog Scale and Portenoy‐6 questions); and depression (Beck Depression Inventory) assessment. QoL measures of FSHD were compared with those of Italian norms. Moreover, we correlated QoL and pain measurements with clinical findings. Sixty‐five patients were enrolled in the study. QoL was statistically significantly reduced with respect to the Italian normative sample, mainly in physical domains. Our study demonstrated that pain is frequent in FSHD patients. More than half of the patients complained of at least moderate pain. Women complained of slightly higher levels of deterioration in the emotional aspects of QoL than men. Clinical pattern (as assessed by Clinical Severity Scale) was closely related to physical QoL domains: the higher the clinical involvement, the more severe the QoL deterioration. This study provided information that may be crucial in clinical practice: pain may be a relevant aspect in FSHD patients, and prevention strategies or relevant therapies should be considered as appropriate. Moreover, we must pay more attention to gender differences: women can suffer far greater deterioration in the emotional aspects of QoL. Further multidimensional observations are needed. Muscle Nerve 40: 200–205, 2009     

Assessment OF aged mdx mice by electrical impedance myography and magnetic resonance imaging

Introduction: Similar to magnetic resonance imaging (MRI), electrical impedance myography (EIM) is dependent on the presence and location of water in muscle to assess neuromuscular diseases. We compared the 2 technologies in mdx mice to better understand their relationship. Methods: EIM and MRI, using T2 relaxation and diffusion‐weighted imaging (DWI), were performed on the gastrocnemius of 10 mdx and 10 wild‐type mice. Muscle function and tissue composition measurements were compared with the EIM and MRI data. Results: EIM reactance and T2 relaxation mapping can discriminate healthy from diseased mice (P < 0.001 for both), but DWI could not. Both T2 relaxation and EIM reactance also correlated closely with muscle function/composition and with each other. Conclusion: Given the low cost of EIM and the simplicity of application, it may be a valuable alternative to muscle MRI in Duchenne muscular dystrophy, where simple cumulative indices of muscle health are being sought. Muscle Nerve 52: 598–604, 2015